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IAP binding compounds

a technology of iap and binding compounds, which is applied in the direction of peptide/protein ingredients, peptide sources, instruments, etc., can solve the problems of short half-life due to proteolytic degradation in the body, lack of molecular specificity of therapies, and inability to disclose or teach structural bases, etc., to achieve easy or less expensive synthesizing, the effect of improving the pharmacologic properties

Inactive Publication Date: 2010-05-18
THE TRUSTEES FOR PRINCETON UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The described compounds effectively bind to IAPs, promoting apoptosis and potentially offering enhanced stability, absorption, and reduced immunogenicity compared to traditional peptides, making them suitable for diagnostic and therapeutic applications in cancer treatment.

Problems solved by technology

However, these therapies lack molecular specificity, and more specific molecular targets are needed.
However, the patent neither discloses nor teaches a structural basis for choosing a particular peptide fragment of Smac for use as a therapeutic agent or target.
These include short half-life due to proteolytic degradation in the body, low absorption through intestinal walls and potential immunogenic reactions, as well as expense involved in peptide synthesis.

Method used

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Examples

Experimental program
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Effect test

example 1

Synthesis of Certain Compounds of the Invention and Components Thereof

[0171]

[0172](4-bromo-butyl)-benzene (50 a) (PAA 2-68). Phosphorus tribromide (1.10 mL, 11.2 mmol) was added dropwise to (4-hydroxy-butyl)-benzene (5.04 g, 33.5 mmol) and stirred 1 h under argon at 23° C. The flask was then heated to 100° C. via silicone oil bath and allowed to stir 4 h. The reaction mixture was cooled, quenched with several mL of cold H2O, diluted with ether, washed with brine (2×20 mL), dried over sodium sulfate, and concentrated in vacuo to 6.32 g (88%) of colorless oil. 1H NMR (CDCl3, 300 MHz) δ 7.18-7.33 (m, 5H), 3.44 (t, J=6.9 Hz, 2H), 2.66 (t, J=6.9 Hz, 2H), 1.76-1.96 (m, 4H); 13C NMR (CDCl3, 75 MHz) δ 147.8, 128.4, 125.8, 35.0, 33.7, 32.2, 29.8.

[0173]

[0174](5-bromo-pentyl)-benzene (50 b) (PAA 67). Phosphorus tribromide (0.47 mL, 5.0 mmol) was added dropwise to (5-hydroxy-pentyl)-benzene (1.98 g, 12.0 mmol) and stirred 1 h under argon at 23° C. The flask was then heated to 100° C. via silico...

example 2

Synthesis of Certain Oxazole Compounds

[0231]Synthetic Scheme for Oxazole Compounds

[0232]

[0233]I. Formation of Boc-Ala-Ser-OMe (3):

[0234]1 eq. of Boc-Ala-succinimide ester (2) was added to an ice-cold solution of DIPEA (2 eq.) and H-Ser-methyl ester hydrochloride (R═H) or H-Thr-methyl ester hydrochloride (R═CH3) (1) in dry THF under argon. The solution was allowed to warm to RT and stirred overnight (Rocchi, R. et al. (1987) Int. J. Peptide Protein Res. 30, 240-256). The THF was removed in vacuo, the resin was brought up in ethyl acetate and washed three times each with saturated sodium bicarbonate, 5% citric acid and saturated sodium chloride. The solution was dried with magnesium sulfate and the solvent was removed in vacuo leaving a white solid. Single spot on TLC (1:10 MeOH / CHCl3). No purification was necessary. 75% yield.

[0235]II. Formation of Boc-Ala-Ser-OMe oxazoline (4):

[0236]1.05 eq. Burgess' reagent was added in one portion to a stirred solution of 3 in dry THF and the resu...

example 3

Synthesis of Compounds Containing Proline or Phenylalanine Derivatives

[0246]Materials. Unless otherwise stated, materials were purchased from Aldrich Chemical Co. (Milwaukee, Wis.) or Fisher Scientific (Pittsburgh, Pa.) and used without further purification. All unnatural phenylalanine derivatives were purchased from Advanced ChemTech (Louisville, Ky.) or Novabiochem (Calbiochem, San Diego, Calif.) as the Fmoc protected amino acid. These and the proline derivatives were used in peptide synthesis in the same manner as a naturally-occurring amino acid would be. Methylbenzhydrylamine (MBHA) solid-phase peptide synthesis resin, Rink amide resin, and 9-Fluorenylmethoxycarbonyl (Fmoc) protected amino acids were obtained from Advanced ChemTech (Louisville, Ky.) and NovaBiochem (San Diego, Calif.). 6-Bromoacetyl-2-dimethylaminonaphthalene (badan) dye was obtained from Molecular Probes (Eugene, Oreg.).

[0247]Peptide synthesis. Peptide molecules were synthesized on an Advanced ChemTech 396 MPS...

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Abstract

Compounds that bind cellular IAPs (inhibitor of apoptosis proteins) are disclosed. The compounds are mimetics of the N-terminal tetrapeptide of IAP-binding proteins, such as Smac / DIABOLO, IIid, Grim and Reaper, which interact with a specific surface groove of IAP. Also disclosed are methods of using these compounds for therapeutic, diagnostic and assay purposes.

Description

[0001]This application is a CIP of PCT / US03 / 22071, filed Jul. 15, 2003 which claims benefit of 60 / 395,918, filed Jul. 15, 2002, the entirety of which is incorporated by reference herein.[0002]This application is a CIP of PCT / US02 / 17342, filed May 31, 2002, which claims benefit of 60 / 294,682, filed May 31, 2001 and 60 / 345,630, filed Jan. 3, 2002. This application is a CIP of 09 / 965,967, filed Sep. 28, 2001, which claims benefit of 60 / 236,574, filed Sep. 29, 2000, and 60 / 256,830, filed Dec. 20, 2000. The entire contents of each of the aforementioned applications are incorporated by reference herein.[0003]Pursuant to 35 U.S.C. §202(c), it is acknowledged that the U.S. Government has certain rights in the invention described herein, which was made in part with funds from the National Institutes of Health, Grant No. GM59348-02.FIELD OF THE INVENTION[0004]The present invention relates to the field of drug design and development for diagnosis, prevention and treatment of cell proliferative...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07K4/00C07K5/00C07K5/06C07K5/097C07K5/103
CPCC07K5/06026G01N33/574C07K5/1008C07K5/0821A61K38/00
Inventor MCLENDON, GEORGEKIPP, RACHAEL A.CASE, MARTINSHI, YIGONGSEMMELHACK, MARTIN F.ALBINIAK, PHILIP A.WIST, AISLYN D.
Owner THE TRUSTEES FOR PRINCETON UNIV
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